MXPA01006224A - Fused 1,2,4-thiadiazine derivatives, their preparation and use - Google Patents

Abstract

The present invention relates to 4H-thieno[3,2-e]-1,2,4-thiadiazine derivatives of general formula (I), compositions thereof and methods for preparing the compounds are described. The compounds are useful in the treatment of diseases of the central nervous system, the cardiovascular system, the pulmonary system, the gastrointestinal system and the endocrinological system.

Description

DERIVATIVES OF 1, 2, 4-TIADIAZINA FUSED, ITS PREPARATION AND USE. FIELD OF THE INVENTION The present invention relates to the 1,2-thiazidine derivatives fused, to the methods for their preparation, to the compositions comprising the compounds, the use of these compounds and medicaments and their use in therapy by example in the treatment or prevention of diseases of the central nervous system, cardiovascular systems, the pulmonary system, the gastrointestinal system and the endocrinological system. Optionally, the pharmaceutical composition of the invention may comprise a compound of formula I combined with one or more pharmacologically active compounds, for example, an antidiabetic and another pharmacologically active material, including compounds for the treatment or prophylaxis of diabetes, including the prevention or retardation of impaired glucose progression by fasting (GRA), and impaired glucose tolerance (TGA), as well as insulin resistance and diseases where insulin resistance is the pathophysiological mechanism. The REF: 129988 suitable antidiabetics comprise short and long acting insulins, insulin analogs as well as orally active hypoglycemic agents such as sulfonylureas, for example, glibenclamide and glipizide, biguanidines, for example, metformin; benzoic acid derivatives, for example repaglinide; thiazolidinediones, for example, troglitazone, rosiglitazone, pioglitazone and ciglitazone; peptide 1 similar to glucagon (GLP-1), GLP-1 derivatives and GLP-1 analogs; a-glucosidase inhibitors, for example, acarbose and voglibose, inhibitors of hepatic enzymes responsible for glucose biosynthesis, for example inhibitors of glycogen phosphorylase. BACKGROUND OF THE INVENTION Potassium channels play an important role in the physiological and pharmacological control of cell membrane potential. Among the different types of channels of potassium are the ATP-sensitive channels (KATP_), which are regulated by changes in the intracellular concentration of adenosine thiophosphate.The KATP- channels have been found in the cells of various tissues such as cardiac cells, pancreatic cells, skeletal muscles, smooth muscles, central neurons and adenohypophysis cells.The channels have been associated with various cellular functions such as hormonal secretion (insulin from pancreatic beta cells, growth hormone and prolactin from the cells of the adenohypophysis), vasodilatation (in the cells of the smooth muscles), the potential duration of the cardiac action, the release of the neurotransmitter in the central nervous system.The modulators of the KATP_ channels have been found to be importance for the treatment of various diseases, certain sulfonylureas, which have been used for the treatment of non-insulin-dependent diabetes mellitus acts by stimulating the release of insulin through inhibition of the KñTP_ channels or pancreatic beta cells. Potassium channel openers, which comprise a heterogeneous group of compounds, have been found to be able to relax vascular smooth muscles and therefore have been used for the treatment of hypertension.

In addition, potassium channel openers can be used as bronchodilators in the treatment of asthma and various other diseases. In addition, potassium channel openers have been shown to promote hair growth, and have been used for the treatment of baldness. The potassium channel openers are also able to relax the smooth muscles of the bladder urinally and also, can be used for the treatment of urinary incontinence. The potassium channel openers, which relax the smooth muscle of the uterus can be used in the treatment of preterm labor. For the activation of the potassium channels of the central nervous system these compounds can be used for the treatment of several neurological and psychiatric diseases such as Alzheimer's, epilepsy and cerebral ischemia. In addition the compounds are found to be useful in the treatment of the onset of prostatic hyperplasia, erectile dysfunction and in contraception.

The compounds of the present invention, which inhibit the secretion of insulin by the activation of the potassium channels of the beta cells can be used in combination with other compounds which can be used for the treatment of non-insulin-dependent diabetes mellitus and insulin-dependent diabetes mellitus, which includes the prevention or retardation of glucose impaired by fasting (GRA), and impaired glucose tolerance (TGA). Examples of such compounds are insulin of short or long activation, insulin analogues, secretory insulin as well as active hypoglycemic agents such as sulfonylureas, for example, glibenclamide and glipzide, biguanidines, for example, metformin, benzoic acid derivatives, example, repaglinide, thiazolidinediones, for example, troglitazone, rosiglitazone, pioglitazone and ciglitazone; peptide 1 similar to glucagon (GLP-1); GLP-1 derivatives and GLP-1 analogues; a-glucosidase inhibitors, for example, acarbose and voglibose, hepatic enzyme inhibitors responsible for glucose biosynthesis, for example, glycogen phosphorylase inhibitors.

After some of the KATP channel openers are able to antagonize vasospasms in basilar or cerebral arteries the compounds of the present invention can be used for the treatment of vasospastic disorders such as subarachnoid hemorrhage and migraine. Potassium channel openers that hyperpolarize neurons and inhibit the release of the neurotransmitter and it is expected that the present compounds can be used in the treatment of various diseases of the central nervous system, for example, epilepsy, ischemia and neurodegenerative diseases, and for the control from pain. Recently, it has been shown that diazoxide derivatives (1,1-dioxide 7-chloro-3-met il-2H-1,2, -benzothiazidine) and certain derivatives of 1,1-dioxide 3- (alkylamino) -4H-pyrido [4, 3-e] -1, 2,4-thiadiazine inhibits insulin release by activation of KñPT channels in pancreatic beta cells. (Pirotte B. Et al. Bi ochem. Pha rma col., 47, 1381-1386 (1994); Pirotte B. Et al., J. Med. Chem. 36 3211-3213 (1993). Diazoxide has also been shown to stop the beginning of diabetes in BB rats (Vlahos WD et al., Metabolism 40, 39-46 (1991)). In obese Zucker rats, diazoxide has been shown to decrease secretion and increase insulin receptor binding and consequently improve tolerance of glucose and decrease the weight again (Alemzadeh R. et al., Endocrinol, 133, 705-712, 1993) .The compounds, which activate the KATP channels can be used for the treatment of diseases characterized by an open production of insulin and for the treatment and prevention of diabetes EP 618 209 discloses a class of pyridothiadiazine derivatives having an alkyl or alkylamino group in the 3-position of the thiadiazine ring These compounds are claimed to be agonists in the AMPA-glutamate In J. Med. Chem. 1980, 23, 575-577 describes the synthesis of 4 (5) -amino- and formylaminoimidazo-5 () carboxamide and its properties as agents of chemotherapeutic value. Especially, the compounds 1,1-dioxide of 3-amino-, 5-dihydro imidazole [4,5-e] -1,2-thiadiazine and 3-benzoylamino-4, 5- 1,1-dioxide are shown dihydroimidazole [4, 5-e] -1, 2,4-thiadiazine.

WO 97/26265 describes a class of 1,2-fused iadiazidine and 1,4-thiazidine derivatives which are useful in the treatment of various diseases. DESCRIPTION OF THE INVENTION The present invention describes the 4H-thieno [3,2-e] -1,2,4-thiadiazine derivatives of the general formula I: wherein: X and Y are independently hydrogen, halogen, perhalomethyl, C? _6 alkyl, C? _6 alkoxy; R1, R2 and R3 are independently C6-6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3-6 cycloalkyl, carboxy, C6_6 alkoxycarbonyl or alkyl, all of which are optionally being mono- or polysubstituted with halogen, hydroxy, oxo , or aril; or R1 is as defined above and R2-C-R3 forms the C3_6 cycloalkyl group, which is optionally mono- or poly-substituted with C6-6 alkyl, perhalomethyl, halogen, hydroxy or aryl; or -CR1R2R3 forms a bicyclic carbocyclic system 0 tricyclic from 4 to 12 members, which is optionally mono- or polysubstituted with alkyl C? -6, perhalomethyl, halogen, hydroxy or aryl, or a salt thereof with a pharmaceutically acceptable acid or base. Within its field the invention includes all optical isomers of the compounds of the formula I, any of it? which are optically active, and also their mixtures which include mixtures thereof. The field of the invention also includes all tautomeric forms of the compounds of formula 1 as well as all metabolites or prodrugs. A "metabolite" of a compound described in this application is an active derivative of a compound described herein which is produced when the compound is metabolized. The metabolites of the compounds described herein can each be identified by the administration of a compound to a host and an analysis of host blood samples, or by incubation of the. compounds with liver cells in vitro and incubation analysis. A "prodrug" is a compound that each becomes a compound described in the application in vivo or has the same active metabolite as a compound described in this application. The salts include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable metal salts or optionally alkylated ammonium salts, such as hydrochloric, hydrobromic, hydrodelic, sulfuric, trifluoroacetic, trichloroacetic, oxalic, maleic, pyruvic, malonic, succinic, citric, tartaric, fumaric. , mandrel, benzoic, cinnamic, methanesulfonicasetanesulfonic, picric and the like and include acids described for the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, 66, 2 (1997) and incorporated herein by reference, or lithium, sodium, potassium, magnesium and the similar. The term "halogen" means fluorine, chlorine, bromine or iodine.

The term "perhalomethyl" means trifluoromethyl, trichloromethyl, t ribrornomethyla or triiodomethyl. The terms "C.sub.6 alkyl." As used herein, alone or in combination, refer to a straight, branched or straight saturated hydrocarbon chain having an indicated number of carbon atoms such as, for example, methyl, ethyl, -propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-methylbutyl, 3-methyltbutyl, 4-methylpentyl, neopentyl, n-hexyl, 1,2-dimethylpropyl , 2,2-dimethylpropyl, 1,2,2-trimethylpropyl and the like The term "C 1-6 alkoxy" as used herein, alone or in combination, refers to a straight or branched monovalent substituent comprising an alkyl group C6 bonded through an ether oxygen having its ether oxygen bond and having from 1 to 6 carbon atoms, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentoxy.

The term "C2_6 alkenyl" as used herein refers to an unsaturated hydrocarbon chain having from 2 to 6 carbon atoms and a double bond such as, for example, vinyl, 1-propenyl, allyl, isopropenyl, n-butenyl , n-pentenyl and n-hexenyl. The term "C2_6 alkynyl" as used herein refers to unsaturated hydrocarbons which contain triple bonds, such as, for example, -CsCH, -C = CCH3, -CH2C = CH, -CH2CH2C = CH, -CH (CH3) C = CH, and the like. The term "Ci-β alkoxycarbonyl" as used herein refers to a monovalent substituent comprising a C ?_6 alkoxy group bonded through a carbonyl group; such as, for example, methoxycarbonyl, carbethoxy, propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, SEQ ID NO-butoxycarbonyl, tert-butoxycarbonyl, 3-methybutoxycarbonyl, n-hexyloxycarbonyl and the like. The term "C_6 cycloalkyl" as used herein refers to a radical of a cyclic hydrocarbon saturated with an indicated number of carbons such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. The term "aryl" as used herein refers to phenyl, 1-naphthyl, or 2-naphthyl.

The term "4 to 12 member tricyclic or bicyclic carbocyclic system" as used herein refers to a monovalent substituent comprising a tricyclic or bicyclic structure made of 4-12 carbon atoms such as, for example, bicyclo [2.1.1] hexane, bicyclo [2.2.1] heptane, bicyclo [2.2.2] octane, octahydropentalene, bicyclo [2.2.0] hexane, adamantane, noradamantane or tricyclo [4.3.1.1 (3.8)) undecane. In one embodiment of the invention X is a halogen, for example chlorine. In another embodiment of the invention Y is hydrogen. In another embodiment of the invention R1, R2 and R3 are C6_6 alkyl. In a further embodiment of the invention R1 is C6_6alkyl, for example methyl or ethyl. In a further embodiment of the invention R1 is carboxy or C6-C6 alkoxycarbonyl, for example carbetoxy. In a further embodiment of the invention R1 is aryl, for example phenyl. In a further embodiment of the invention R2-C-R3 forms a C3_e cycloalkyl group, ie a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group. In a further embodiment of the invention CR1R2R3 forms a tricyclic carbocyclic system, for example adamantane. The specific compounds of the invention are: 3-tert-butylamino-6-chloro-4H-thieno [3, 2-e] -1,2,4-thiadiazine 1,1-dioxide, 6-chloro-3- (1-1,1-dioxide) , 1-dimethylpropylamino) -4H-thieno [3,2-e] -1,2,4-thiadiazine, 6-chloro-3- (1-meth ilcyclopropyl) -amino-4H-thieno 1,1-dioxide [ 3, 2-e] -1, 2, -thiadiazine, 6-chloro-3- (2-hydroxy-l, 1-dimet and leti lamino) -4H-thieno [3, 2-e ] -1, 2, 4-thiadiazine, 6-chloro-3- (1, 1, 3, 3-tetramethylbutylamino) -4H-thieno [3, 2-e] -1, 2, 4 1,1-dioxide -thiadiazine. Other specific compounds of the invention are: 3- (1-adamantyl) amino-6-chloro-4H-thieno [3,2-e] -1,2,4-thiadiazine 1,1-dioxide, ethyl ester of the 1- (6-Chloro-1,4-dihydro-1,1-dioxo-thieno [3,2-e] -l6,2,4,4-thiadiazin-3-ylamino) -cyclopropanecarboxylic acid 1,1- 6-chloro-3- (1-methyl-1-phenylethyl) amino-4H-thieno [3, 2-e] -1,2,4-thiadiazine dioxide, 6-chloro-3-dioxide dioxide - (1-hydroxymethylcyclopentyl) amino-4H-thieno [3,2-e] -1,2,4-thiadiazine, 1- (6-chloro-1,4-dihydro-l, 1-dioxo-thieno] acid 3, 2-e] -l? 6, 2, 4 -thiadiaz-3-ylamino) -cyclopropanecarboxylic, 6-chloro-3- (1-methyl-cyclobutyl) amino-4H-1,1-dioxide -thien [3, 2-e] -1, 2, 4-thiadiazine, 6-chloro-3- (1-methyl-cyclohexyl) amino-4H-thieno [3, 2-e] - 1,1-dioxide 1, 2, 4-thiadiazine, 6-chloro-3- (1-methyl-cyclopentyl) amino-4H-thieno [3,2- e] -1,2,4-thiadiazine 1,1-dioxide, 1 1-6-chloro-3- (1-ethylcyclobutyl) amino-4H-thieno [3,2-e] -1,2,4-thiadiazine dioxide. The compounds of the present invention interact with the potassium channels, which make them useful in the treatment of various diseases of the cardiovascular system, for example cerebral ischemia, hypertension, ischemic heart diseases, angina pectoris and coronary heart diseases, pulmonary system, the gastrointestinal system, the central nervous system and the endocrinological system. Since some of the KATP openers are capable of antagonizing vasospasms in basilar or cerebral arteries the compounds of the present invention can be used in the treatment of vasospastic disorders such as subarachnoid hemorrhage and migraine. The compounds of the present invention can also be used for the treatment of diseases associated with decreased skeletal muscle blood flow such as Reynauds disease and intermittent claudication. In addition, the compounds of the invention can be used for the treatment of diseases of the respiratory tract, including asthma, and for the treatment of detrusor muscle instability secondary to obstruction of the bladder effusion and thus for stones in the kidney, helping its passage through the urethra.

The present compounds can also be used for the treatment of conditions associated with disturbances in gastrointestinal motility such as irritable bowel syndrome. Additionally, these compounds can be used for the treatment of premature labor and dysmenorrhea. Potassium channel openers hyperpolarize neurons and inhibit the release of the neurotransmitter and it is expected that such compounds can be used in the treatment of various diseases of the central nervous system., for example, epilepsy, ischemia and neurodegenerative diseases, and for pain control. In addition, potassium channel openers promote hair growth, in this manner, the compounds of the present invention can be used for the treatment of baldness. The potassium channel openers also relax the smooth muscle of the urinary bladder, thus, the compounds of the present invention can be used for the treatment of urinary incontinence. li In diseases such as nesidioblastosis and insulinoma wherein hypersecretion of insulin causes severe hypoglycemia, the compounds of the present invention can be used to reduce insulin secretion. In obesity, hyperinsulinemia and insulin resistance are very frequently found. This condition can lead to the development of non-insulin dependent diabetes (NIDDM), the potassium channel openers, and therefore the compounds of the present invention, can be used to counteract hyperinsulinemia and thereby prevent diabetes and reduce the Obesity, in the manifest NIDDM treatment of hyperinsulinemia with potassium chain openers, and consequently the compounds present, may be of benefit in the restoration of glucose sensitivity and normal insulin secretion. In this way, the compounds of the present invention can be used in the treatment of NIDDM. In many cases of insulin-dependent diabetes (IDDM) or in prediabetic cases, the potassium channel openers and therefore the present compounds can be used to introduce remains of pancreatic beta cells which can prevent the progression of diseases autoimmune The potassium channel openers of the present invention can be administered in combination with an immunosuppressant or with a similar agent to nocotinamide, which will reduce the autoimmune degeneration of the beta cells. The rest of the beta cells combined with a treatment protects beta cells against the deterioration / cytotoxicity of beta cells mediated by cytokines is a further aspect of this invention. The requirement for insulin or Type 1 diabetes (IDDM) as well as the late onset of IDDM (also known as type 1.5, for example, Type 2 patients who do not require insulin (NIDHR) with autoreactivity against beta-cell epitopes. later they return to the insulin requirement) they have circulating self-reactive monocytes / lymphocytes that harbor islet / beta cells and release their cytokines. Some of these cytokines (eg, interleukin-lb (IL-lb), a tumor necrosis factor a (TNFa) and an inferred g (IFNg) are specifically toxic to beta cells, for example, through the induction of nitric oxide (NO) and other free radicals The inhibition of this cytotoxicity, for example, by the co-administration of nicotinamide (NA), a derivative thereof or other cotcocin protective compounds for prediabetic / diabetic patients treated with the PCO compound is an example in this regard.Nicotinamide belongs to the family of vitamin B and is derived from nicotinic acid by the amidation of the carboxyl group.Processes none of the pharmacological properties of nicotine.A NA is converted to NAD +, which acts as a coenzyme for the proteins that surround tissue respiration, NA has been proposed for several influences of the putative intracellular molecular events followed by the immune attack in the beta cells. Animal experiments and experiments not easily blinded in humans have indicated a protective role of this compound against IDDM as well as in the destruction of beta cells mediated by cytokine / immune. Yet another aspect of this application concerns the use of a PCO compound alone or in combination with the inhibitor of cytokine / immune mediated beta cell damage, in transplantation, for example, islet transplantation in diabetic patients. The use of one or both of these treatments may reduce the risk of rejection of islets / beta cells / beta cells designed by engineering / pancreas. The compounds of the present invention, which act as blockers of the KATP channels, can be used for the treatment of NIDDM. The compounds of the present invention can be used for the treatment or prevention of diseases of the endocrinological system such as hyperinsulinemia and diabetes, which include the prevention or delay of impaired glucose progression by fasting (IFG) and impaired glucose tolerance (IGT). Accordingly, in another aspect the invention discloses a compound of the general formula I or an acid addition, pharmaceutically acceptable salt thereof, for use as a therapeutically acceptable substance, preferably for use as a therapeutically acceptable substance in the treatment of hyperinsulinemia and the treatment or prevention of diabetes, NIDDM and the prevention of impaired glucose progression by fasting (IFG) and impaired glucose tolerance (IGT). Furthermore, the invention also describes the use of the inventive compounds of formula I as useful medicaments for the treatment of hyperinsulinemia and the treatment or prevention of diabetes, NIDDM and the prevention or retardation of impaired glucose progression by fasting ( IFG) and impaired glucose tolerance (IGT). In this manner, the pharmaceutical composition of the invention may comprise a compound of formula I combined with one or more other pharmacologically active compounds, for example, an antidiabetic or other pharmacologically active material. Suitable antidiabetics comprise short or long activation insulins, insulin analogues as well as orally active hypoglycemic agents such as sulfonylureas, for example, glibenclamide and glipizide; biguanidines, for example metformin, benzoic acid derivatives, for example, repaglinide; thiazolidinediones, for example, troglitazone, rosiglitazsna, pioglitazone and ciglitazone; peptide 1 similar to glucagon (GLP-1), GLP-1 derivatives and GLP-1 analogs; a-glucosidase inhibitors, for example, acarbose and voglibose, inhibitors of hepatic enzymes responsible for glucose biosynthesis, for example, inhibitors of glycogen phosphorylase. In still another aspect, the present invention describes the methods of preparation of the compounds mentioned above. The methods comprise: a) reacting a compound of formula II: wherein X and Y are as defined above and Z is a leaving group such as alkoxy, alkylthio, trimethylamino, methylsulfinyl, methylsulfonyl or halogen, preferably chlorine, bromine or iodine, more preferably fluorine or chlorine, with a compound of formula III: wherein R1, R2 and R3 are as defined above to form a compound of the general formula I using the procedures described by, for example, T.H. Cron et al., J. Med. Chem. 11, 136 (1968); L. Raffa et al., Drug Ed. Sci. 29 411 (1974); B. Pirotte et al., J. Med. Chem, 36, 3211 (1993); b) reacting a compound of formula IV; wherein X and Y are as defined above, with a compound of formula III, or a suitable salt thereof in the presence of P205 and a high boiling tertiary amine or a suitable salt thereof using a procedure described by Jensen K.G. and Pedersen E.B. Chem. Ser., 20, 248-250 (1998) and Andersen L., Nielsen F.E. and Pedersen E.B., Chem. Ser. 29, 45-49 (1989) to form a compound of general formula I; c) reacting a compound of formula IV; wherein X and Y are as defined above with a compound of formula III, or a suitable salt thereof in the presence of titanium tetrachloride and a solvent with which it can form a complex, similar to for example, or a mixture of toluene and anisole, according to the methods described in Rl Fryer, J. V. Earley, G.F. Field, W. Zally, and L.H. Sternbach, J. Org. Chem. 34, 1143-1145 (1969); J.B. Press et al., J. Med. Chem, 22 725-731 (1979); or G. Roma et al., Eur. J. Chem. 26, 489-496 (1991), to form a compound of the general formula I; d) reacting a compound of formula V wherein X and Y are as defined above, with a compound of formula VI wherein R1, R2 and R3 are as defined above using the method described by Chem. J.W. et al., J. Heterocycl. Chem, 27 1909-1915 (1990), to form a compound of the general formula I; e) reacting a compound of formula V wherein X and Y are as described above, with a compound of formula VII wherein R1, R2 and R3 are as defined above using the method described by Chem J.W. et al., J. Heterocycl. Chem, 27 1909-1915 (1990), to form a compound of the general formula I; f) reacting in the presence of a base a compound of formula VIII or a suitable salt thereof, wherein X and Y are as defined above and R4 is hydrogen or R5OC (= 0), wherein R5 is C6-alkyl, with a compound of formula IX (IX) wherein R1, R2 and R3 are as defined above, to form an adduct which may have either of the two structures X or XI or be a mixture of the two either by ring closure, for example, by treatment with phosgene in a suitable solvent, forms a compound of the general formula I, if R4 is hydrogen, and a compound of the "general formula XII if R4 is R50C (= 0 ), wherein R5 is C6_6 alkyl; g) hydrolyzing and subsequently decarboxylating a compound of the general formula XII to form a compound of the general formula I, for example by heating the starting compound in an aqueous base. The starting materials each are known compounds which can be prepared in analogy with the preparation of known compounds or in analogy with known methods as described by, for example, Huang B.-S., et al., J. Med.

Chem., 23 575-7 (1980), Ofitserov V.I. et Khim.

Geterotsiki. Soedin, 1119-22 (russ.) (1976), Topliss J.G .., U.S. 3,641,017 (1972), Kotovskaya S.K. et al., Khim-Farm. Zh., 13, 54-57 (russ) (1979), Meyer R.F., J. Heterocycl. Chem., 6, 407-408 (1969) and Hattori M., Yoneda M., and Goto M., Bull. Chem. Soc. Jap., 46, 1890-1 (1973), Williams T.R. and Cram D.J., J.. Org. Chem., 38, 20-26 (1973), Barnes A.C. Kennewell P.D. and Taylor J.B., J. Chem. Soc. Chem. Common., 1973, 776-777., Stoss and Satzinger, Chem. Ver., 109, 2097 (1976), Kresze G., Hatjiissaak A., Phosphorus Sulfur, 29, 41-47 (1987), Dillard RD, Yen TT, Stark P., Pavey DE, J. Med. Chem., 23, 717-722 (1980). PHARMACOLOGICAL METHODS The ability of compounds to interact with potassium channels can be determined by several methods. When patch-fastener techniques are used (Hamill OP, Marty A., Neher E., Sakmann B. and Sigworth FJ Plugers Arch., 391, 85-100 (1981)), the ionic current can be recorded through a single channel of a cell. The activity of the compounds as potassium channel openers can be measured as the relaxation of the aortic rings of the rat to the following procedure: A section of the thoracic aorta of the rat between the aortic arch and the diaphragm is dissected and assembled as ring preparations as described by Taylor P.D. et al., Brit J. Pha rma col 111, 42-48 (1994). After 45 minutes, the equilibrium period under a tension of the preparations is contracted to achieve 80% of the maximum response using the required concentration of phenylephrine. When the response of phenylephrine reaches the plateau, potential vasodilatory agents were added cumulatively to the bath in small volumes using molar increments of logarithm at 2 minute intervals. Relaxation is expressed in a percentage of the contracted tension. The potency of a compound is expressed as the concentration required to evoke a 50% relaxation of the tissue. In pancreatic beta cells, the opener of the KñTp channels can be determined by measuring the subsequent change in the concentration of a free cytoplasmic Ca 2+ concentration according to the method of Arkhammar P. et al., J. Biol. Chem., 262 5448-5454 (1987).

The effect of a KATP channel opener and a KATP channel blocker on pancreatic beta cells can be determined by measuring the 86Rb + evacuation of a β cell line according to the following method. Evacuation of 86Rb + from a ß cell line. The RIN 5F cell line was grown in RPMI 1640 with Glutamax I, supplemented with 10% fetal calf serum (from GibcoBRL, Scotland, UK) and maintained at an atmosphere of C02 5% / air 95% a 37 ° C. the cells are separated with a solution of Trypsin-EDTA (from GibcoBRL, Scotland, UK) are resuspended in a medium, 1 mCi / ml 86Rb + is added and coated in microtitre plates (96 wells group 3596, sterile, from Costar Corporation, MA, USA) a density of 50000 cells / well in 100 μl / well, and grown 24 hours before being used in the assay. The plates are washed 4 times with a Ringer buffer (150 mM NaCl, lOmM Hepes, 3.0 mM KCl, 1.0 mM CaCl2, 20 mM sucrose, pH 7.1), eighty μl of the Ringer buffer and 1 μl of the control compound is added. or test dissolved in DMSO. After incubation for 1 hour at room temperature with a lid, 50 μl of the supernatant is transferred to PicoPlacas (Packard Instrument Company, CT, USA) and 100 μl of MicroScint 40 (Packard Instrument Company, CT, USA) is added. The plates are counted in TopCount (Packard Instrument Company, CT, USA) for 1 min / well in the 32P program. The calculation of EC50 is done by SideWrite (Advanced Graphics Software, Inc., CA, USA) using a four-parameter logistic curve; y = (ad) (1+ (x / c) b) + d, where a = the activity estimated at the zero concentration, b = a slope factor, c = the concentration in the middle of the curve y, d = the estimated activity in the infinite concentration, EC5o = cy Emax = d, when the curve is returned in the infinite concentrations. The effect of modulators of the KATP channel on pancreatic beta cells can be determined by measuring the quantitative changes in the membrane potential of the cell line that produces β-TC3 insulin using fluorescent imaging techniques. The potential DIBAC fluorescent membrane test is used. The cells are preserved in a buffer solution -HEPES Ca2 + supplemented with 10 mM glucose. After 5 s of each run of 60 s the compound is added. 48 wells are run in each batch, taking about 1 hour. The same cells then run again, now 25 mM KCl is added after 5 s, and the depolarization induced in the DIBAC fluorescence monitored for 55 s is increased. In addition, the effect of KATP channel modulators on pancreatic beta cells can be determined by measuring the increase or decrease in the release of insulin from the insulin produced by the beta cell lines or isolated islets. The effect of KATP channel modulators can be measured by using the following procedure: Beta cells are cultured with medium changes every three to four days. The cells are then seeded in 96 well microtitre plates and cultured for three days at 38 ° C, 5% C02 and 95% humidity. Cells are washed with NN buffer (+ 10 mM Hepes + 0.1% BSA) for one minute and glucose is added (final conc 22 mM), IBMX (final conc 0.1 mM) and compounds (conc. 5 x 10 ~ 5 M - 5 x 10 M). All cells are then incubated for three hours (38 ° C, 5% C02 and 95% humidity). The supernatants are collected in minisorb microtiter well and frozen. Insulin is measured using ELISA techniques. The compounds of the present invention show a high potency in the insulin release test and a high selectivity compared to the relaxation of the rat aortic ring test. PHARMACEUTICAL COMPOSITIONS The present invention also relates to pharmaceutical compositions comprising, as an active ingredient, at least one of the compounds of the general formula I or a pharmaceutically acceptable salt thereof and, usually, said compositions also contain a pharmaceutically acceptable acceptable carrier. or diluent. Pharmaceutical compositions comprising a compound of the present invention may be prepared by conventional techniques, for example, as described in Remington: The Science and Practice of Pharmacy 19th Ed., 1995. The compositions may appear in conventional forms, for example capsules , tablets, aerosols, solutions, suspensions or topical applications. Typical compositions include a compound of formula I or a pharmaceutically acceptable acid addition salt thereof, associated with a pharmaceutically acceptable excipient which can be a carrier, or a diluent or which is diluted by means of a carrier, which includes within a carrier which may be in the form of a capsule, sack, paper or other container. In the embodiment of the compositions, conventional techniques for the preparation of pharmaceutical compositions can be used. For example, the active compound will usually be mixed with a carrier, or diluted by means of a carrier, or it will be included within a carrier, which can be in the form of an ampule, capsule, sack, paper, or other container . When the carrier serves as a diluent, it can be solid, semi-solid, or liquid material, which acts as a vehicle, excipient, or a medium for the active compound. The active compound can be absorbed in a solid granular solid container such as a sack. Examples of suitable carriers are water, saline solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, syrup, peanut oil, olive oil, gelatin, lactose, gypsum, sucrose, cyclodextrin, amylose, magnesium stearate, talc. , gelatin, agar, pectin, acacia, stearic acid or low alkyl ethers of cellulose, cylilic acid, fatty acids, fatty acid amines, monoglycerides and diglycerides of fatty acids, fatty acid esters pentaerythritol, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone. Similarly, the carrier or diluent may include any prolonged release material known in the art, such as glyceryl monoestearate or glyceryl dieterate, alone or mixed with a wax. The formulations may include wet agents, emulsifying and dispersing agents, preservatives, sweetening agents or flavoring agents. The formulations of the invention can be formulated to provide a delayed, prolonged or rapid release of the active ingredient after administration to the patient by employing procedures well known in the art. The pharmaceutical preparations can be sterilized and mixed, if desired, with auxiliary agents, emulsifiers, salt for influencing the osmotic pressure, buffers and / or coloring substances and the like, which do not react perniciously with the active compounds. The route of administration can be any, which effectively transports the active compound to the desired or appropriate site of action, such as, for example, oral, nasal, pulmonary, transdermal or parenteral administration, for example, rectal, in deposits, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, local, ophthalmic solution or an ointment, the oral route is preferred. If the solid carrier is used for oral administration, the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form or it can be in the form of a troche or lozenge. If the liquid carrier is used, the preparation may be in the form of syrups, emulsions, soft gelatin capsules or sterile injectable liquids such as a non-aqueous or aqueous liquid suspension or a solution. For nasal administration, the preparation may contain a compound of formula I dissolved or suspended in a liquid carrier, in particular an aqueous carrier, for the application of aerosol. The carrier may contain additives such as solubilizing agents, for example propylene glycol, surfactants, absorption enhancers such as lecithin (phosphat idylcholine) or cyclodextrin, or preservatives such as parabens. For parenteral application, particularly injectable solutions or suspensions are suitable, aqueous solutions with the active compound dissolved in polyhydroxylated castor oil are preferred. Tablets, dragees, or capsules having talc and / or a carbohydrate carrier or a binder or the like are particularly suitable for oral application. Preferred carriers for tablets, dragees, or capsules include lactose, corn starch, and / or potato starch. A syrup or elixir can be used in cases where a sweetening vehicle can be used. A typical tablet, suitable for use in this method, can be prepared by conventional tabletting techniques and contains: Active Compound 5.0 mg Lactosum 67.8 mg Ph.Eur. Avicel® 31.4 mg Amberlite® 1.0 mg Magnesii stearas 0.25 mg Ph.Eur. The compounds of the invention can be administered to a mammal especially to a human being in need of such treatment, prevention, elimination, alleviation or amelioration of various diseases as mentioned above, especially diseases of the endocrinological system, such as hyperinsulinemia and diabetes . Such mammals also include animals, domestic animals, for example pets of the home, and non-domestic animals such as wild animals. The compounds of the invention may be administered in the form of an alkali metal or a metal salt of alkaline earth thereof, concurrently, simultaneously or together with a pharmaceutically acceptable carrier or diluent, especially and preferably in the form of a pharmaceutical composition of the invention. same, in an effective amount. The compounds according to the invention are effective over a wide range of doses. For example, in the treatment of humans, the doses are from about 0.05 to about 1000 mg, preferably from about 0.1 to about 500 mg and a compound of formula I, conveniently provided from 1 to 5 times per day . A more preferable dose is from about 1 to about 100 mg per day. The exact dose will depend on the mode of administration, the form in which it is administered, the subject to be treated and the body weight of the subject to be treated, and the preference and experience of the attending physician or veterinarian. Generally, the compounds are distributed in the form of unit doses comprising from about 1 to about 100 mg of the compounds of formula I in or together with a pharmaceutically acceptable carrier per unit dose. Usually, the dosage forms suitable for 4 Oral, nasal, pulmonary or transdermal administration comprises from about 0.05 mg to about 1000 mg, preferably from about 0.1 mg to about 500 mg of the compounds of formula I administered with a pharmaceutically acceptable carrier or diluent. Any new aspect or combination of the aspects described herein are considered essential for this invention. EXAMPLES The process for preparing the compounds of formula I are further illustrated in the following examples which, however, are not constructed as limiting. EXAMPLE 1 1-tert-Butylamino-6-chloro-4H-thieno [3,2-e] -1,2,4-thiadiazine dioxide A solution of 3,6-dichloro 1,1-dioxide is stirred -4H-thieno [3, 2-e] -1,2,4-thi diazine (5.0 g, 19.45 mmol in tert-butylamine (20 mL, 0.19 mol) for 20 hours at 125 ° C in a sealed flask. The cold solution is concentrated in vacuo and the residue is stirred with water (25 ml) followed by adjustment to a pH of 2 with 4M hydrochloric acid.The resulting precipitate is isolated by filtration, washed with water, and redissolved in sodium hydroxide IN (130 ml) followed by treatment with decolorizing carbon After filtration, the clear solution is acidified to pH 2 and the precipitate is filtered and recrystallized from methanol to provide 2.91 g (52%) of the pure titre, mp 368-372 ° C; 1H-MNR (DMSO-d6): d 1.37 (s, 9H), 6.79 (br s, ÍH); MS: m / e 293/295 (M +); (C9H12CI1O2S2 ) cale C 36.79 H 4.12 N 14.30 Cl 12.07 S 21.83, is C 36.90 H 4.11 N 14.8 Cl 1 2.05 S 21.89.

EXAMPLE 2 1, 1-6-Chloro-3- (1,1-dimethylpropylamino) -4H-thieno [3,2-e] -1,2,4-thiadiazine dioxide A solution of 1,1-dioxide of 3,6-dichloro-4H-t-ene [3, 2-e] -1, 2,4-thiadiazine (5.0 g, 19. 45 mmol) in 1,1-dimethylpropylamine (10 ml, 85.7 mmol) for 30 hours at a temperature of 125 ° C in a sealed flask. The cold solution is concentrated in vacuo and the residue is stirred with water (25 ml) followed by adjustment to a pH of 2 with 4M hydrochloric acid. The resulting precipitate is isolated by filtration, washed with water, and redissolved by a slight heating in IN sodium hydroxide (130 ml) followed by treatment with decolorizing carbon. After filtration, the clear solution is acidified to pH 2 and the precipitate is filtered and recrystallized from methanol to provide 3.38 g (56%) of the pure title compound; mp of 359-360 ° C; 1H-MNR (DMSO-d6): d 0.82 (t, 3H), 1.31 (s, 6H), 1.73 (q, 2H), 6.67 (br s, ÍH), 7.12 (s, lH), 10.57 (br s, ÍH); MS: m / e 307/309 (M +); (C? 0H? 4N3Cl? O2S2) cale. C 39.02 H 4.58 N 13.65 Cl 11.52 S 20.83, is C 39.10 H 4.58 N 13.48 Cl 11.69 S 20.97.

EXAMPLE 3 1, 6-Chloro-3- (1-methyl-cyclopropyl) amino-4H-thieno [3,2-e] -1,2,4-thiadiazine dioxide A solution of 1.1 is stirred 3,6-dichloro-4H-thieno [3, 2-e] -1,2,4-thiadiazine dioxide (386 mg, 1.5 mmol) in 1-methylocyclopropylamine (1.0 g, 14 mmol) for 24 hours at 85 ° C in a sealed flask. The cold Aolution is concentrated in vacuo and the residue is stirred with ethyl acetate (1-2 mL) and filtered. The white precipitate is stirred in 4M hydrochloric acid (50 ml) for 2 hours and then filtered and purified by chromatography on silica gel with ethyl acetate to give 112 mg (26%) of the pure title compound; mp 251-252 ° C dec; xH-MNR (DMSO-de): d 0.65-0.79 (m, 4H), 1.36 (s, 3H), 7.11 (s, ÍH), 7.82 (br s, ÍH), 10.78 (br s, ÍH); MS: m / e 291/293 (M +); (C9H? 0N3Cl? O2S2) cale. C 37.05 H 3.45 N 14.40, C is C 36.96-H 3.53 N 14.15.

EXAMPLE 4 1, 1-dioxide of 6-chloro-3- (2-hydroxy-l, l-dimet i leti lamino) -4 H -thieno [3,2- e] -1,2,4-thiadiazine One is stirred solution of 3,6-dichloro-4H-thieno 1,1-dioxide [3,2-e] -1,2,4-thiadiazine (0.3 g, 1.17 mmol) in 2-amino-2-methyl-l- propanol (2 ml, 21 mmol) for 40 hours at 120 ° C in a sealed flask. Water (5 ml) is added to the cold solution and the pH is adjusted to < 2 by the addition of 4M hydrochloric acid. The resulting precipitate is isolated by filtration, washed with water, and recrystallized from methanol / water to provide 51 mg (14%) of the pure title compound; mp 224-226 ° C; XH-MNR (DMSO-d6): d 1.30 (s, 6H), 3.43 (s, 2H), 5.17 (br s, 1H), 6.63 (br s, ÍH), 7.10 (s, ÍH) 10.90 (s, 1 HOUR); MS: m / e 309/311 (M +).

EXAMPLE 5 1, 1-6-Chloro-3- (1,1,3,3-tetramethyl-butylamino) -4H-thieno [3,2-e] -1,2-thiadiazine A solution is stirred of 3,6-dichloro-4H-thieno [3, 2-e] -1,2,4-thiadiazine 1,1-dioxide (0.5 g, 1.95 mmol) in 1, 1, 3, 3-tetramethyl-butylamine (5 mi, 31 mmol) for 44 hours at a temperature of 120 ° C in a sealed flask. Water (25 ml) is added to the cold solution and the pH is adjusted to < 2 by the addition of 4M hydrochloric acid. The resulting precipitate is isolated by filtration, washed with water, and then redissolved in IN sodium hydroxide (15 ml) at a temperature of 50-60 ° C followed by the decolorizing carbon treatment. After filtration, the clear solution is acidified to pH 2 by the addition of 4M hydrochloric acid and the precipitate is filtered and recrystallized from methanol to give 207 mg (31%) of the pure title compound; mp 369-371 ° C decAH-MNR (DMSO-d6): d 0.98 (s, 9H), 1.42 (s, 6H), 1.86 (s, 2H), 6.75 (br s, lH), 7.12 ( s, lH), 10.55 (s, lH); MS: m / e 349/351 (M +); (C10H20N3Cl? O2S2) cale. C 44.63 H 5.76 N 12.01 is C 44.74 H 5.78 N 11.84. EXAMPLE 6 1- (1-Adamant-il) amino-6-chloro-4H-thieno [3,2-e] -1,2,4-thiadiazine dioxide A mixture of 1,1-dioxide is stirred of 3,6-dichloro-4H-thieno [3,2-e] -1,2,4-thiadiazine (1.0 g, 3.9 mmol), 1-adamantanamine hydrochloride (1.46 g, 7.8 mmol) and triethylamine (1.1 ml) , 7.8 mmol) in ethanol (6 ml) for 41 hours at a temperature of 120 ° C in a sealed flask. The cold solution is concentrated in vacuo and the residue is stirred with water (50 ml) followed by adjustment to a pH < 2 with 4M hydrochloric acid. The resulting dark mass is isolated by means of decanting and then partially dissolved in hot IN sodium hydroxide (50 ml) followed by treatment with decolorizing carbon. After filtration, the solution is acidified to a pH < 2 and the precipitate is filtered and recrystallized from ethanol to provide 160 mg (11%) of the title compound as a beige colored solid; mp 339-340 ° C; XH-MNR (DMS0-d5): d 1.64 (br s, 6H), 2. ~ 02 (br s, 6H), 2.06 (br s, 3H), 6.67 (br s, lH), 7.10 (s , lH), 10.55 (br s, lH); MS: m / e 371/373 (M +); (C? 5H? 8ClN302S2) cale. C 48.44 H 4.88 N 11.30 is C 48.27 H 4.85 N 11.15.

EXAMPLE 7 1- (6-Chloro-1,4-dihydro-1,1-dioxo-thieno [3,2-e] -l-6,2,4-thiadiazin-3-ylamino) -cyclopropanecarboxylic acid ethyl ester • A mixture of 1,1-dioxide, 3,6-dichloro-4H-thieno [3,2-e] -1,2,4-thiadiazine (1.0 g, 3.9 mmol), hydrochloride of the ethyl ester of the acid is stirred. 1-aminocyclopropanecarboxylic acid (1.29 g, 7.8 mmol) and triethylamine (1.1 ml, 7.8 mmol) in ethanol (6 ml) for 23 hours at a temperature of 120 ° C in a sealed flask. The cold solution is concentrated in vacuo and the residue is triturated with water followed by adjustment to a pH < 2 with 4M hydrochloric acid. The resulting dark crude material is isolated by filtration and purified by chromatography (ethyl acetate) to provide 151 mg (11%) of the title compound; mp 190-19 ° C (dec); ^ -MNR (DMSO-d6): d 1.15 (t, 3H), 1.22 (m, 2H), 1.50 (m, 2H), 4.09 (q, 2H), 7.06 (s, ÍH), 8.14 (br s, ÍH), 11.14 (br s, ÍH); MS: m / e 349/351 (M +).

EXAMPLE 8 Acid (6-chloro-l, 1-dioxo-1,4-dihydro-thieno [3,2-e] -1,5,6,4,4-thiadiazin-3-ylamino) -cyclopropanecarboxylic acid A mixture of 3,6-dichloro-4H-thieno [3,2-e] -1,2,4-thiadiazine 1,1-dioxide (1.0 g, 3.9 mmol), 1-aminocyclopropanecarboxylic acid ethyl ester hydrochloride (1.29) g, 7.8 mmol) and triethylamine (1.1 ml, 7.8 mmol) in ethanol (6 ml) for 23 hours at a temperature of 120 ° C in a sealed flask. The cold solution is concentrated in vacuo and the residue is triturated with water followed by adjustment to a pH < 2 with 4M hydrochloric acid. The resulting dark crude material is isolated by filtration and boiled in 1 N sodium hydroxide followed by the decolorizing carbon treatment. After filtration, the solution is acidified to a pH <; 2 with 4M hydrochloric acid and the precipitate is filtered and recrystallized from ethanol to provide 354 mg (28%) of the title compound; mp 299-300 ° C (dec) AH-MNR (DMSO-d6): d 1.17 (br s, 2H), 1.49 (br s, 2H), 7.09 (s, ÍH), 8.1 (br s, ÍH) , 11.15 (br s, ÍH), 12.7 (br s, ÍH); MS: m / e 303/305 (M-H20) A Example 9 1,1-chloro-3- (1-hydroxymethylcyclopentyl) amino-4H-thieno [3, 2-e] -1, 2-dioxide, 4-thiadiazine A mixture of 3,6-dichloro-4H-t-ene [3, 2-e] -1,2,4-thiadiazine (0.5 g, 1.95 mmol) and (1-aminociclopentyl) -methanol (0.45) is stirred. g, 3.9 mmol) in ethanol (4 ml) for 21 hours at a temperature of 120 ° C in a sealed flask. The cold solution is concentrated in vacuo and the residue is dissolved in IN sodium hydroxide (40 ml) followed by treatment with decolorizing carbon. After filtration, the clear solution is acidified to a pH < 2 with 4M hydrochloric acid and the precipitate is filtered and recrystallized from ethanol and finally purified by means of chromatography (dichloromethane / methanol (19: 1)) to provide 70 mg (10%) of the title compound; mp of 213-214 ° C; XH-MNR (DMSO-d6): d 1.45-2.0 (m, 8H), 3.53 (s, 2H), 5.05 (br s, ÍH), 6.82 (br s, ÍH), 7.1? (s, ÍH), 10.8 (br s, 1H); MS: m / e 335/337 (M +), 317/319 (M-H20) EXAMPLE 10 1, 6-Chloro-3- (1-methyl-1-phenylethyl) amino-4H-thieno [3,2-e] -1,2,4-thiadiazine dioxide A mixture of 1 is stirred 1-dioxide of 3,6-dichloro-4H-thieno [3,2-e] -1,2,4-thiadiazine (1.0 g, 3.9 mmol) and cumylamine (1.06 g, 7.8 mmol) in ethanol (6 ml) ) for 31 hours at a temperature of 120 ° C in a sealed flask. The cold solution is concentrated in vacuo and the residue is dissolved in sodium hydroxide (50 ml) followed by the decolorizing carbon treatment. After filtration, the clear solution is acidified to a pH < 2 with 4M hydrochloric acid and the precipitate is filtered and recrystallized from ethanol to provide 278 mg (20%) of the title compound; mp ca 360 ° C (decomposes gradually above 200 ° C); ^ -MNR (DMSO-d6): d 1.68 (s, 6H), 7.12 (s, ÍH), 7.17-7.41 (m, 6H), 10.72 (br s, ÍH); MS: m / e 355/357 (M +); (C? 4H14CIN302S2) cale C47.25 H3.97 N11.81, is C46.82 H3.96 Nll.62. EXAMPLE 11 1, 1-6-Chloro-3- (1-methylcyclohexyl) amino-4H-thieno [3,2-e] -1,2,4-thiadiazine a) 1,1-chloro-6-dioxide 3-fluoro-4H-t-ene [3, 2-e] -1,2,4-thiadiazine A mixture of 1,1-dioxide of 3,6-dichloro-4H-thieno [3, 2-e] is stirred. ] -1, 2, 4-thiadiazine (257 mg, .1.0 mmol) and cesium fluoride (456 mg, 3.0 mmol) in Dry DMSO (1 mL) is stirred for 16 hours at a temperature of 155 ° C in a sealed flask. Water (3 mL) is added to the cold mixture followed by acidification with 4M hydrochloric acid at a pH < 2.

The beige precipitated solid is isolated by filtration, washed with water and dried to provide 193 mg (80%) of the title compound; 1H-MNR (DMSO-de): d 7.09 (s, ÍH), 7.34 (br s, ÍH; MS: m / e 240/242 (+)). b) 6-Chloro-3- (1-methylcyclohexyl) amino-4H-thieno [3, 2-e] -1, 2, 4-tiadiazine 1,1-dioxide A mixture of 1.1 is stirred 6-chloro-3-fluoro-4H-thieno [3,2-e] -1,2,4-thiadiazine dioxide (0.5 g, 2.08 mmol) and 1-methyl-cyclohexylamine hydrochloride (373 mg, 4.16 mmol) in ethanol (3 ml) for 20 hours at a temperature of 50 ° C and then for 22 hours at a temperature of 100 ° C in a sealed flask. The cold mixture is concentrated in vacuo and the residue is triturated with water followed by adjustment to a pH < 2 with 4M hydrochloric acid. The crude product is isolated by filtration and dissolved in IN sodium hydroxide followed by treatment with decolorizing carbon. After filtration, the solution is acidified to a pH < 2 with 4M hydrochloric acid and the precipitate is filtered and purified by chromatography (dichloromethane / methanol (19: 1)). Recrystallization from ethanol gives 55 mg (8%) of the pure title compound; mp 218-219 ° C; H-MNR (DMSO-de): d 1.18-1.54 (m, 11H), 1.97-2.12 (m, 2H), 6.55 (br s, ÍH), 7.12 (s, ÍH), 10.60 (br s, ÍH) .

EXAMPLE 12 1, 6-Chloro-3- (1-meth i 1-cyclopentyl) amino-4H-thieno [3,2-e] -1,2,4-thiadiazine dioxide A mixture of 1.1 is stirred 6-chloro-3-fluoro-4H-thieno [3, 2-e] -1,2,4-thiadiazine dioxide (0.60 g, 2.5 mmol), 1-meth ilcyclopentyl amine hydrochloride (1.5 g, 3.7 mmol) ) and triethylamine (1.0 ~ 3 mL, 7.4 mmol) in ethanol (2.5 mL) for 16 hours at a temperature of 50 ° C and then for 24 hours at a temperature of 65 ° C in a sealed flask. The cold mixture is concentrated in vacuo and the residue is triturated with water followed by adjustment to a pH < 2 with 1M hydrochloric acid. The crude product is isolated by filtration, dried and recrystallized from acetic acid to provide 208 mg (26%) of the title compound; pf > 300 ° C (dec); ^ -MNR (DMSO-d6): d 1..43 (s, ÍH), 1.53-1.72 (m, 6H), 1.92-2.10 (m, 2H), 6.91 (br s, ÍH), 7.10 (s, ÍH) 10.52 (br s, ÍH).

EXAMPLE 13 1, 1-6-Chloro-3- (1-methylcyclobutyl) amino-4H-thieno [3, 2-e] -1, 2,4-t-diadiazine A mixture of 1,1-dioxide is stirred of 6-chloro-3-fluoro-4H-t-ene [3, 2-e] -1, 2,4-thiadiazine (1.3 g, 5.3 mmol), 1-methylocyclobutylamine hydrochloride (1.0 g, 8.1 mmol) and triethylamine (2.5 ml, 18.1 mmol) in ethanol (10 ml) for 16 hours at a temperature of 50 ° C and then for 5 hours at a temperature of 70 ° C in a sealed flask. The cold mixture is concentrated in vacuo and the residue is triturated with water (25ml) followed by adjustment to pH <.; 2 with ÍM hydrochloric acid. The crude product is isolated by filtration, recrystallized from acetic acid and finally purified by chromatography (C18; 20-60% acetonitrile + 0.01% TFA) to provide 363 mg (22%) of the title compound; mp 294-296 ° C; ^ -MNR (DMSO-d6): d 1.48 (s, 3H), 1.75-1.88 (m, 2H), 1.94-2.05 (m, 2H), 2.18-2.31 (m, 2H), 7.08 (s, ÍH) , 7.33 (br s, ÍH) 10.67 (br s, ÍH); LC-MS: m / e 306/308 (M + 1) EXAMPLE 14 1, 1-6-Chloro-3- (1-methylcyclobutyl) amino-4H-thieno [3, 2-e] -1, 2, 4-thiadiazine A mixture of 1,1-dioxide, 3,6-dichloro-4H-thieno [3,2-e] -1,2,4-thiadiazine (1.02 g, 3.95 mmol), fluoride, is stirred. potassium (688 mg, 11.9 mmol) and hexadecyltrimethylammonium bromide (43 mg, 0.12 mmol) in 1-met il-2-pyrrolidinone (4 mL) for 20 hours at a temperature of 130 ° C under nitrogen to form a 6-membered dioxide. -chloro-3-fluoro-4H-thieno [. { 3, 2-e] -1, 2, 4-thiadiazine. The mixture is allowed to cool to room temperature and then reacts directly with 1-ethylcyclohexylamine hydrochloride (0.8g, 5.93 mmol) and triethylamine (1.65 ml, 11.9 mmol) for 30 hours at a temperature of 75 ° C in a sealed flask. The cold mixture is poured into water, acidified to a pH < 2 using IN hydrochloric acid and extracted with ethyl acetate. The organic phase is dried with sodium sulfate and evaporated to dryness to give the pure title compound; mp 244-246 ° C; 2H-MNR (DMSO-de): d 0.79 (t, 3H), 1.70-1.93 (m, 8H), 1.96-2.08 (m, 2H), 2.13-2.25 (m, 2H), 7.09 (s, ÍH) , 7.24 (br s, ÍH) 10.57 (br s, ÍH).

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (33)

1. CLAIMS Having described the invention as above, the content of the following claims is declared as property: 1. A compound of general formula I: characterized in that X and Y are independently hydrogen, halogen, perhalomethyl, C? _6 alkyl, Ci-? alkoxy, "R1, R2 and R3 are independently C? -6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3_6 cycloalkyl, carboxy, Ci-e alkoxycarbonyl or alkyl, all of which are optionally being mono- or polysubstituted with halogen, hydroxy, oxo, or aryl, or R1 is as defined above and R2-C-R3 forms the C6 cycloalkyl group , which is optionally mono- or pilosubstituted with C6-6 alkyl, perhalomethyl, halogen, hydroxy or aryl; or -CR1R2R3 forms a bicyclic or tricyclic carbocyclic system of 4 to 12 members, which is optionally mono- or poly-substituted with C-alkyl ? -6, perhalomethyl, halogen, hydroxy or aryl, or a salt thereof with a pharmaceutically acceptable acid or base including all optical isomers of the compounds of formula I, some of which are optically active, and also their mixtures that include rac mixtures emic, or any tautomeric form thereof.
2. 2. A compound according to claim 1 characterized in that, X is a halogen and Y is hydrogen.
3. 3. A compound according to claim 2, characterized in that X is chlorine.
4. 4. A compound according to any of the preceding claims characterized in that R1, R2 and R3 are all C6_6 alkyl.
5. 5. A compound according to any of the preceding claims, characterized in that R1 is C6-6-6 alkyl.
6. A compound according to claim 5, characterized in that R1 is methyl.
7. 7. A compound according to any of the preceding claims, characterized in that R2-C-R3 form a C3_6 cycloalkyl group.
8. 8. A compound according to any of the preceding claims, characterized in that -CR1R2R3 forms a tricyclic carbocyclic system.
9. 9. A compound according to any of the preceding claims, characterized in that the C? -6 alkyl group is substituted with a hydroxy.
10. 10. A compound according to any of the claims, characterized in that it is selected from the following: 1,1-dioxide 3-tert-butylamino-6-chloro-4H-thieno [3, 2-e] -1, 2, thiadiazine; 6-chloro-3- (1,1-dimethylpropylamino) -4H-thieno [3,2-e] -1,2,4-thiadiazine 1,1-dioxide; 6-chloro-3- (1-methylcyclopropyl) amino-4H-thieno [3,2-e] -1,2,4-thiadiazine 1,1-dioxide; 6-chloro-3- (2-hydroxy-1,1-dimethylethylamine) -4H-thieno [3,2-e] -1,2,4-thiadiazine 1,1-dioxide 1,1-dioxide -chloro-3- (1, 1, 3, 3-tetramet-tylamino) -4H-thieno [3,2-e] -1,2,4-thia'diazine. or a salt thereof with a pharmaceutically acceptable acid or base, including all optical isomers of the compounds of formula I, some of which are optically active, and also mixtures thereof including racemic mixtures, or any tautomeric form thereof .
11. 11. A compound according to any of the preceding claims 1-9 selected from the following: 3- (1-adamantyl) amino-6-chloro-4H-thieno 1,1-dioxide [3, 2-e] -1, 2, 4-thiadiazine, 1- (6-chloro-l, 4-dihydro-l, l-dioxo-thieno [3,2-e] -l 6, 2,4-thiadiazin) ethyl ester -3-i lamino) -cyclopropanecarboxylic acid, 6-chloro-3- (1-methyl-1-phenylethyl) amino-4H-thieno [3, 2-e] -1,2,4-thiadiazine 1,1-dioxide , 6-chloro-3- (1-hydroxymethylcyclopentyl) amino-4H-thieno [3,2-e] -1,2,4-thiadiazine 1,1-dioxide, l- (6-chloro-l, 4) -dihydro-l, l-dioxo-thieno [3, 2-e] -l? 6, 2,4-thiadiazin-3-ylamino) -cyclopropanecarboxylic acid, 1,1-dioxide of 6-chloro-3- (1- methyl-cyclobutyl) amino-4H-thieno [3,2-e] -1,2,4-thiadiazine, 6-chloro-3- (1-methyl-cyclohexyl) amino-4H-thieno 1,1-dioxide 3, 2-e] -1, 2, 4-thiadiazine, 6-chloro-3- (1-methyl-cyclopentyl) amino-4H-thieno [3,2-e] -l, 2-1,1-dioxide , 4-thiadi zine, 6-chloro-3- (1-ethylcyclobutyl) amino-4H-tie 1,1-dioxide no [3, 2-e] -1, 2, 4 -thiadiazine; or a salt thereof with a pharmaceutically acceptable acid or base, including all optical isomers of the compounds of formula I, some of which are optically active, and also their mixtures including racemic mixtures, or any tautomeric form of the same.
12. 12. The compounds according to any of the preceding claims, characterized in that they act as openers of the potassium channels regulated by KATP.
13. A pharmaceutical composition, characterized in that it comprises a compound according to any of claims 1-12 or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base, or any isomer or mixture of optical isomers, including a mixture racemic, or any tautomeric form together with one or more pharmaceutically acceptable carriers or diluents.
14. 14. A pharmaceutical composition for use in the treatment of diseases of the endocrinological system such as hyperinsulinemia and diabetes, comprising a compound according to any of claims 1-12 or a pharmaceutically acceptable salt thereof with an acid or base pharmaceutically acceptable, or any isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form together with one or more pharmaceutically acceptable carriers or diluents.
15. 15. A pharmaceutical composition for use in the treatment or prevention of non-insulin-dependent diabetes mellitus, characterized in that it comprises a compound according to any of claims 1-12 or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base. , or any isomer or optical mixture of the optical isomers, including a racemic mixture, or any tautomeric form together with one or more pharmaceutically acceptable carriers or diluents.
16. 16. A pharmaceutical composition for use in the treatment of impaired impaired glucose progression (IFG) and impaired glucose tolerance (IGT), characterized in that it comprises a compound according to any of claims 1 -12 or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base, or an optical isomer or mixture of the optical isomers, including a racemic mixture, or any tautomeric form together with one or more pharmaceutically acceptable carriers or diluents.
17. 17. A pharmaceutical composition according to claims 13 to 16, characterized in that it is in the form of an oral dose unit or parenteral dosage unit.
18. 18. A pharmaceutical composition according to claims 13 to 16, characterized in that said compound is administered as a dose in the range of about 0.05 to 1000, preferably from about 0.1 to 500 and specifically in the range of 50 to 200 mg per day.
19. 19. A compound according to one of claims 1-12 or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form for its therapeutic use
20. 20. A compound according to one of claims 1-12 or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form for its use in the treatment or prevention of diseases of the endocrinological system, such as hyperinsulinemia and diabetes.
21. 21. A compound according to one of claims 1-12 or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form for its use in the treatment or prevention of diabetes mellitus not dependent on insulin.
22. 22. A compound according to one of claims 1-12 or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form for its use in the treatment of rapidly impaired glucose progression (GFR) and impaired glucose tolerance (IGT).
23. 23. A compound according to one of claims 1-12 or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form as a medicine •
24. 24. The use of a compound according to one of claims 1-12 for the preparation of a medicament.
25. 25. The use of a compound according to any one of claims 1-12 or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form for the preparation of a medicament for the treatment or prevention of diseases of the endichronological system, such as hyperinsulinemia and diabetes.
26. 26. The use of a compound in accordance with any one of the rei indications 1-12 or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base., or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form for the preparation of a medicament for the treatment or prevention of non-insulin-dependent diabetes mellitus.
27. 27. The use of a compound according to any one of claims 1-12 or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form for the preparation of a medicament for the treatment of impaired glucose progression by fasting (IFG) and impaired glucose tolerance (IGT).
28. 28. A method for the treatment or prevention of diseases of the endocrinological system, such as hyperinsulinemia and diabetes in a subject in need thereof, characterized in that it comprises the administration of an effective amount of a compound according to any of claims 1-12. to a subject.
29. 29. A method for the treatment or prevention of non-insulin-dependent diabetes mellitus in a subject in need thereof, characterized in that it comprises administering an effective amount of a compound according to claims 1-12 to said subject.
30. 30. A method for the treatment of impaired glucose progression by fasting (IFG) and impaired glucose tolerance (IGT) in a subject in need thereof characterized in that it comprises the administration of an effective amount of a conforming compound. with any of claims 1-12 to said subject. 3Í.
31. A process for the manufacture of a medicament, particularly for use in the treatment or prevention of diseases of the endocrinological system, such as hyperinsulinemia and diabetes, characterized in that the process comprises carrying a compound of formula I in accordance with any of the claims 1-12 or a pharmaceutically acceptable salt thereof in a dosage dosage form.
32. 32. The methods for the preparation of the compounds of the formula I according to claim 1, characterized in that it comprises: a) reacting a compound of formula II: wherein X and Y are as defined above and Z is a leaving group such as alkoxy, alkylthio, triethylamine, methylsulfinyl, methylsulfonyl or halogen, preferably chlorine, bromine or iodine, more preferably fluorine or chlorine, with a compound of formula III : wherein R1, R2 and R3 are as defined above to form a compound of the general formula I, or b) reacting a compound of formula IV; (IV) wherein X and Y are as defined above, with a compound of formula III, wherein R1, R2 and R3 are as defined above or a suitable salt thereof in the presence of P2Os and a high boiling tertiary amine or a suitable salt thereof, to form a compound of general formula I, or c) reacting a compound of formula IV; wherein X and Y are as defined above with a compound of formula III, wherein R1, R2 and R3 are as defined above or a suitable salt thereof in the presence of titanium tetrachloride and its solvent with which a complex, similar for example to tetrahydrofuran, or a mixture of toluene and anisole, can be formed, for forming a compound of the general formula I, or d) reacting a compound of formula V wherein X and Y are as defined above, with a compound of formula VI wherein R1, R2 and R3 are as defined above, to form a compound of the general formula I; or e) reacting a compound of formula V wherein X and Y are as described above, with a compound of formula VII wherein R1, R2 and R3 are as defined above, to form a compound of the general formula I; or f) reacting in the presence of a base a compound of formula VIII or a suitable salt thereof, wherein X and Y are as defined above and R4 is hydrogen or R5OC (= 0), wherein R5 is alkyl • 1-6, with a compound of formula IX wherein R1, R2 and R3 are as defined above, to form an adduct which may have each of the two structures X or XI or be a mixture of the two either by ring closure, for example, by treatment with phosgene in a suitable solvent, they form a compound of the general formula I, if R4 is hydrogen, and a compound of the general formula XII if R4 is R5OC (= 0) , wherein R5 is Ci-6 alkyl; g) hydrolyzing and subsequently decarboxylating a compound of the general formula XII to form a compound of the general formula I, for example by heating the starting compound in an aqueous base.
33. 33. Any novel aspect or combination of aspects as described here.